DNMT3A clonal hematopoiesis is associated with cardiovascular disease in women

Background Clonal hematopoiesis (CH) is an independent risk factor for cardiovascular disease (CVD). Targeted next generation sequencing (NGS) studies have highlighted the contribution of smaller clones to CVD, particularly for DNMT3A and TET2 CH, the most frequent CH mutations. DNMT3A CH occurs more frequently in women than men. Whether sex affects the association between CH and CVD is unknown. Methods We included 5,508 participants from the Lifelines cohort, who had previously undergone targeted NGS. Our cohort is enriched for blood count abnormalities. We investigated the sex-specific associations between CH and prior myocardial infarction (MI) or coronary artery calcium (CAC) and evaluated the association of sex or prior MI with clonal expansion. Results We identified 2,103 participants carrying CH. DNMT3A CH occurred more frequently in women than men (OR 1.29; p =5.2x10 -4 ). Women with DNMT3A CH had a higher odds of prior MI (OR 1.77; p =2.1x10 -2 ), while men did not (OR 0.98; p =8.8x10 -1 ; P interaction =4.4x10 -2 ). Sex or prior MI did not affect clonal expansion. DNMT3A clone size positively associated with age- and sex-adjusted CAC percentile scores in women (B 28.97; p =9.7x10 -3 ), but not in men (B 2.34; p =8.3x10 -1 ; P interaction =8.9x10 -2 ). Women with a higher-than-average DNMT3A clonal expansion had higher CAC percentile scores compared to women with lower-than-average clonal expansion, independent of initial DNMT3A clone size (B 16.76; p =1.1x10 -2 ). Conclusions DNMT3A CH is associated with previous MI and higher atherosclerotic burden only in women, highlighting the need to better understand the sex-specific risks that CH may confer on CVD.